Neurochemical Research

, Volume 42, Issue 7, pp 2071–2076 | Cite as

Can Neurochemical Changes of Mood Disorders Explain the Increase Risk of Epilepsy or its Worse Seizure Control?

  • Andres M. Kanner
Original Paper


The existence of a bidirectional relation between mood disorders and epilepsy has been suggested by six population-based studies. Furthermore, three studies have associated a higher risk of treatment-resistant epilepsy with a history of depression preceding the onset of epilepsy. Common pathogenic mechanisms operant in depression and epilepsy may provide a possible explanation of these observations. This article reviews some of the leading pathogenic mechanisms of depression with respect to potential proconvulsant properties that may provide explanations for these phenomena.


Major depressive disorders Glutamate GABA Serotonin Cortisol Treatment-resistant epilepsy 


  1. 1.
    Lewis A (1934) Melancholia: a historical review. J Ment Sci 80:1–42Google Scholar
  2. 2.
    Forsgren L, Nystrom L (1990) An incident case-referent study of epileptic seizures in adults. Epilepsy Res 6:66–81CrossRefPubMedGoogle Scholar
  3. 3.
    Hesdorffer DC, Hauser WA, Ludvigsson P, Olafsson E, Kjartansson O (2006) Depression and attempted suicide as risk factors for incident unprovoked seizures and epilepsy. Ann Neurol 59:35–41CrossRefPubMedGoogle Scholar
  4. 4.
    Hesdorffer DC, Hauser WA, Annegers JF, Cascino G (2000) Major depression is a risk factor for seizures in older adults. Ann Neurol 47:246–249CrossRefPubMedGoogle Scholar
  5. 5.
    Hesdorffer DC, Ishihara L, Mynepalli L, Webb DJ, Weil J, Hauser WA (2012) Epilepsy, suicidality, and psychiatric disorders: a bidirectional association. Ann Neurol 72:184–191CrossRefPubMedGoogle Scholar
  6. 6.
    Jossephson CB, Lowerison M, Vallerand I, Sajobi TT, Patten S, Jette N, Wiebe S (2017) Association of depression and treated depression with epilepsy and seizure outcomes: a multicohort analysis. JAMA Neurol. doi: 10.1001/jamaneurol.2016.5042 Google Scholar
  7. 7.
    Hitiris N, Mohanraj R, Norrie J et al (2007) Predictors of pharmacoresistant epilepsy. Epilepsy Res 75:192–196CrossRefPubMedGoogle Scholar
  8. 8.
    Petrovski S, Szoeke CEI, Jones NC, Salzberg MR, Sheffield LJ, Huggins RM et al (2010) Neuropsychiatric symptomatology predicts seizure recurrence in newly treated patients. Neurology 75:1015–1021CrossRefPubMedGoogle Scholar
  9. 9.
    Kanner AM, Byrne R, Chicharro A et al (2009) A lifetime psychiatric history predicts a worse seizure outcome following temporal lobectomy. Neurology 72:793–799CrossRefPubMedGoogle Scholar
  10. 10.
    Cleary RA, Thompson PJ, Fox Z, Foong J (2012) Predictors of psychiatric and seizure outcome following temporal lobe epilepsy surgery. Epilepsia 53(10):1705–1712CrossRefPubMedGoogle Scholar
  11. 11.
    de Araújo Filho GM, Gomes FL, Mazetto L, Marinho MM, Tavares IM, Caboclo LO et al (2012) Major depressive disorder as a predictor of a worse seizure outcome one year after surgery in patients with temporal lobe epilepsy and mesial temporal sclerosis. Seizure 8:619–623CrossRefGoogle Scholar
  12. 12.
    Kanner AM (2012) Can neurobiological pathogenic mechanisms of depression facilitate the development of seizure disorders? Lancet Neurol 11(12):1093–1102CrossRefPubMedGoogle Scholar
  13. 13.
    Kanner AM, Mazarati A, Koepp M (2014) Biomarkers of epileptogenesis: psychiatric comorbidities (?) Neurotherapeutics 11(2):358–372CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Sanacora G, Mason GF, Rothman DL, Krystal JH (2002) Increased occipital cortex GABA concentrations in depressed patients after therapy with selective serotonin reuptake inhibitors. Am J Psychiatry 159:663–665CrossRefPubMedGoogle Scholar
  15. 15.
    McCullumsmith RE, Meador-Woodruff JH (2002) Striatal excitatory amino acid transporter transcript expression in schizophrenia, bipolar disorder, and major depressive disorder. Neuropsychopharmacology 26:368–375CrossRefPubMedGoogle Scholar
  16. 16.
    Zarate CA, Quiroz J, Payne J, Manji HK (2002) Modulators of the glutamatergic system: implications for the development of improved therapeutics in mood disorders. Psychopharmacol Bull 36:35–83PubMedGoogle Scholar
  17. 17.
    Levine K, Panchalingam K, Rapaport S, Gershon S, McClure RJ, Pettegrew JW (2000) Increased cerebrospinal fluid glutamine levels in depressed patients. Biol Psychiatry 47:586–593CrossRefPubMedGoogle Scholar
  18. 18.
    Kugaya A, Sanacora G (2005) Beyond monoamines: glutamatergic function in mood disorders. CNS Spectr 10:808–819CrossRefPubMedGoogle Scholar
  19. 19.
    Mitani H, Shirayama Y, Yamada T, Maeda K, Ashby CR Jr, Kawahara R (2006) Correlation between plasma levels of glutamate, alanine and serine with severity of depression. Prog Neuropsychopharmacol Biol Psychiatry 30:1155–1158CrossRefPubMedGoogle Scholar
  20. 20.
    Hashimoto K, Sawa A, Iyo M (2007) Increased levels of glutamate in brains of patients with mood disorders. Biol Psychiatry 25:1310–1316CrossRefGoogle Scholar
  21. 21.
    Zink M, Vollmayr B, Gebicke-Haerter PJ, Henn FA (2010) Reduced expression of glutamate transporters vGluT1, EAAT2 and EAAT4 in learned helpless rats, an animal model of depression. Neuropharmacology 58:465–473CrossRefPubMedGoogle Scholar
  22. 22.
    Berman RM, Cappiello A, Anand A et al (2000) Antidepressant effects of ketamine in depressed patients. Biol Psychiatry 47:351–354CrossRefPubMedGoogle Scholar
  23. 23.
    Zarate CA Jr, Singh JB, Carlson PJ et al (2006) A randomized trial of an N-methyl-d-aspartate antagonist in treatment-resistant major depression. Arch Gen Psychiatry 63(8):856–864CrossRefPubMedGoogle Scholar
  24. 24.
    Preskorn SH, Baker B, Kolluri S, Menniti FS, Krams M, Landen JW (2008) An innovative design to establish proof of concept of the antidepressant effects of the NR2B subunit selective N-methyl-d-aspartate antagonist, CP-101,606, in patients with treatment refractory major depressive disorder. J Clin Psychopharmacol 28:631–637CrossRefPubMedGoogle Scholar
  25. 25.
    Bonanno G, Giambelli R, Raiteri L et al (2005) Chronic antidepressants reduce depolarization-evoked glutamate release and protein interactions favoring formation of SNARE complex in hippocampus. J Neurosci 25:3270–3279CrossRefPubMedGoogle Scholar
  26. 26.
    Gerner RH, Hare TA (1981) CSF GABA in normal subjects and patients with depression, schizophrenia, mania, and anorexia nervosa. Am J Psychiatry 138:1098–1101CrossRefPubMedGoogle Scholar
  27. 27.
    Sanacora G, Mason GF, Rothman et al (1999) Reduced cortical gamma-aminobutyric acid levels in depressed patients determined by proton magnetic resonance spectroscopy. Arch Gen Psychiatry 56:1043–1047CrossRefPubMedGoogle Scholar
  28. 28.
    Sanacora G, Gueorguieva R, Epperson et al (2004) Subtype-specific alterations of gammaaminobutyric acid and glutamate in patients with major depression. Arch Gen Psychiatry 61:705–713CrossRefPubMedGoogle Scholar
  29. 29.
    Bhagwagar Z, Wylezinska M, Jezzard et al (2007) Reduction in occipital cortex gammaaminobutyric acid concentrations in medication-free recovered unipolar depressed and bipolar subjects. Biol Psychiatry 61:806–812CrossRefPubMedGoogle Scholar
  30. 30.
    Sanacora G, Mason GF, Rothman DL et al (2003) Increased cortical GABA concentrations in depressed patients receiving ECT. Am J Psychiatry 160:577–579CrossRefPubMedGoogle Scholar
  31. 31.
    Davies CH, Davies SN, Collingridge GL (1990) Paired-pulse depression of monosynaptic GABA-mediated inhibitory postsynaptic responses in rat hippocampus. J Physiol 424:513–531CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Prendiville S, Gale K (1993) Anticonvulsant effect of fluoxetine on focally evoked limbic motor seizures in rats. Epilepsia 34(2):381–384CrossRefPubMedGoogle Scholar
  33. 33.
    Mazarati AM, Siddarth P, Baldwin RA, Sankar R (2008) Depression after status epilepticus: behavioural and biochemical deficits and effects of fluoxetine. Brain 131:2071–2083CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Clinckers R, Smolders I, Meurs A et al (2004) Anticonvulsant action of hippocampal dopamine and serotonin is independently mediated by D2 and 5-HT1A receptors. J Neurochem 89:834–843CrossRefPubMedGoogle Scholar
  35. 35.
    Dailey JW, Mishra PK, Ko KH, Penny JE, Jobe PC (1992) Serotonergic abnormalities in the central nervous system of seizure-naive genetically epilepsy-prone rats. Life Sci 50:319–326CrossRefPubMedGoogle Scholar
  36. 36.
    Lopez-Meraz ML, Gonzalez-Trujano ME, Neri-Bazan L, Hong E, Rocha LL (2005) 5-HT1A receptor agonists modify seizures in three experimental models in rats. Neuropharmacology 49:367–375CrossRefPubMedGoogle Scholar
  37. 37.
    Meldrum BS, Anlezark GM, Adam HK et al (1982) Anticonvulsant and proconvulsant properties of viloxazine hydrochloride: pharmacological and pharmacokinetic studies in rodents and the epileptic baboon. Psychopharmacology 76:212–217CrossRefPubMedGoogle Scholar
  38. 38.
    Piette Y, Delaunois AL, De Shaepdryver AF et al (1963) Imipramine and electroshock threshold. Arch Int Pharmacodyn Ther 144:293–297PubMedGoogle Scholar
  39. 39.
    Brennan TJ, Seeley WW, Kilgard M, Schreiner CE, Tecott LH (1997) Sound-induced seizures in serotonin 5-HT2c receptor mutant mice. Nat Genet 16(4):387–390CrossRefPubMedGoogle Scholar
  40. 40.
    Yan QS, Jobe PC, Dailey JW (1995) Further evidence of anticonvulsant role for 5-hydroxytryptamine in genetically epilepsy prone rats. Br J Pharmacol 115:1314–1318CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Alper K, Schwartz KA, Kolts RL, Khan A (2007) Seizure incidence in psychopharmacological clinical trials: an analysis of Food and Drug Administration (FDA) summary basis of approval reports. Biol Psychiatry 62(4):345–354CrossRefPubMedGoogle Scholar
  42. 42.
    Favale E, Audenino D, Cocito L, Albano C (2003) The anticonvulsant effect of citalopram as an indirect evidence of serotonergic impairment in human epileptogenesis. Seizure 12(5):316–318CrossRefPubMedGoogle Scholar
  43. 43.
    Favale E, Rubino V, Mainardi P, Lunardi G, Albano C (1995) The anticonvulsant effect of fluoxetine in humans. Neurology 45:1926CrossRefPubMedGoogle Scholar
  44. 44.
    Specchio LM, Iudice A, Specchio N, La Neve A, Spinelli A, Galli R et al (2004) Citalopram as treatment of depression in patients with epilepsy. Clin Neuropharmacol 27(3):133–136CrossRefPubMedGoogle Scholar
  45. 45.
    Ribot R, Ouyang B, Kanner AM (2017) The impact of antidepressants on seizure frequency and depressive and anxiety disorders of patients with epilepsy: is it worth investigating? Epilepsy Behav 70(Pt A):5–9. doi: 10.1016/j.yebeh.2017.02.032.CrossRefPubMedGoogle Scholar
  46. 46.
    Toczek MT, Carson RE, Lang L (2003) PET imaging of 5-HT1A receptor binding in patients with temporal lobe epilepsy. Neurology 60:749–756CrossRefPubMedGoogle Scholar
  47. 47.
    Hasler G, Bonwetsch R, Giovacchini G (2007) 5-HT(1A) receptor binding in temporal lobe epilepsy patients with and without major depression. Biol Psychiatry 62:1258–1264CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Savic I, Lindstrom P, Gulyas B, Halldin C, Andree B, Farde L (2004) Limbic reductions of 5-HT1A receptor binding in human temporal lobe epilepsy. Neurology 62:1343–1351CrossRefPubMedGoogle Scholar
  49. 49.
    Sargent PA, Kjaer KH, Bench CJ et al (2000) Brain serotonin 1 A receptor binding measured by positron emission tomography with [11C]WAY-100635: effects of depression and antidepressant treatment. Arch Gen Psychiatry 57:174–180CrossRefPubMedGoogle Scholar
  50. 50.
    Maes M (1999) Major depression and activation of the inflammatory response system. Adv Exp Med Biol 461:25–45CrossRefPubMedGoogle Scholar
  51. 51.
    Parsadaniantz SM, Batsche E, Gegout-Pottie P et al (1997) Effects of continuous infusion of interleukin 1 beta on corticotropin-releasing hormone (CRH), CRH receptors, proopiomelanocortin gene expression and secretion of corticotropin, beta-endorphin and corticosterone. Neuroendocrinology 65:53–63CrossRefPubMedGoogle Scholar
  52. 52.
    Dunn AJ, Swiergiel AH (2005) Effects of interleukin-1 and endotoxin in the forced swim and tail suspension tests in mice. Pharmacol Biochem Behav 81:688–693CrossRefPubMedPubMedCentralGoogle Scholar
  53. 53.
    Brambilla D, Franciosi S, Opp MR, Imeri L (2007) Interleukin-1 inhibits firing of serotonergic neurons in the dorsal raphe nucleus and enhances GABAergic inhibitory post-synaptic potentials. Eur J Neurosci 26:1862–1869CrossRefPubMedGoogle Scholar
  54. 54.
    Vezzani A, Balosso S, Ravizza T (2008) The role of cytokines in the pathophysiology of epilepsy. Brain Behav Immun 22:797–803CrossRefPubMedGoogle Scholar
  55. 55.
    Vezzani A, Moneta D, Conti M et al (2000) Powerful anticonvulsant action of IL-1 receptor antagonist on intracerebral injection and astrocytic overexpression in mice. Proc Natl Acad Sci USA 97:11534–11539CrossRefPubMedPubMedCentralGoogle Scholar
  56. 56.
    Crespel A, Coubes P, Rousset MC et al (2002) Inflammatory reactions in human medial temporal lobe epilepsy with hippocampal sclerosis. Brain Res 952:159–169CrossRefPubMedGoogle Scholar
  57. 57.
    Boer K, Jansen F, Nellist M et al (2008) Inflammatory processes in cortical tubers, and subependymal giant cell tumors of tuberous sclerosis complex. Epilepsy Res 78:7–21CrossRefPubMedGoogle Scholar
  58. 58.
    Ravizza T, Boer K, Redeker S et al (2006) The IL-1β system in epilepsy-associated malformations of cortical development. Neurobiol Dis 24:128–143CrossRefPubMedGoogle Scholar
  59. 59.
    Mazarati AM, Pineda E, Shin D, Tio D, Taylor AN, Sankar R (2010) Comorbidity between epilepsy and depression: role of hippocampal interleukin-1β. Neurobiol Dis 37:461–467CrossRefPubMedGoogle Scholar
  60. 60.
    Pineda EA, Hensler JG, Sankar R, Shin D, Burke TF, Mazarati AM (2011) Plasticity of presynaptic and postsynaptic serotonin 1 A receptors in an animal model of epilepsy-associated depression. Neuropsychopharmacology 36:1305–1316CrossRefPubMedPubMedCentralGoogle Scholar
  61. 61.
    Bockaert J, Marin P (2015) Neuroinflammatory mechanisms: mTOR in brain physiology and pathologies. Physiol Rev 95(4):1157–1187CrossRefPubMedGoogle Scholar
  62. 62.
    Jernigan CS, Goswami DB, Austin MC, Iyo AH, Chandran A, Stockmeier CA, Karolewicz B (2011) The mTOR signaling pathway in the prefrontal cortex is compromised in major depressive disorder. Prog Neuropsychopharmacol Biol Psychiatry 35:1774–1779CrossRefPubMedPubMedCentralGoogle Scholar
  63. 63.
    French JA, Lawson JA, Yapici Z, Ikeda H, Polster T, Nabbout R et al. (2016) Adjunctive everolimus therapy for treatment-resistant focal-onset seizures associated with tuberous sclerosis (EXIST-3): a phase 3, randomised, double-blind, placebo-controlled study. Lancet 388:2153–2163CrossRefGoogle Scholar
  64. 64.
    Evans DL, Charney D (2003) Mood disorders and medical illness: a major public health problem. Biol Psychiatry 54:177–180CrossRefPubMedGoogle Scholar
  65. 65.
    Salzberg M, Kumar G, Supit L, Jones NC, Morris MJ, Rees S et al (2007) Early postnatal stress confers enduring vulnerability to limbic epileptogenesis. Epilepsia 48:2079–2085CrossRefPubMedGoogle Scholar
  66. 66.
    Jones NC, Kumar G, O’Brien TJ, MorrisMJ, Rees SM, Salzberg MR (2009) Anxiolytic effects of rapid amygdala kindling, and the influence of early life experience in rats. Behav Brain Res 12(203):81–87CrossRefGoogle Scholar
  67. 67.
    Karst H, de Kloet ER, Joëls M (1999) Episodic corticosterone treatment accelerates kindling epileptogenesis and triggers long-term changes in hippocampal CA1 cells, in the fully kindled state. Eur J Neurosci 11:889–898CrossRefPubMedGoogle Scholar
  68. 68.
    Taher TR, Salzberg M, Morris MJ, Rees S, O’Brien TJ (2005) Chronic low-dose corticosterone supplementation enhances acquired epileptogenesis in the rat amygdala kindling model of TLE. Neuropsychopharmacology 30:1610–1616CrossRefPubMedGoogle Scholar
  69. 69.
    Kumar G, Couper A, O’Brien TJ, Salzberg MR, Jones NC, ReesSM et al (2007) The acceleration of amygdala kindling epileptogenesis by chronic low-dose corticosterone involves both mineralocorticoid and glucocorticoid receptors. Psychoneuroendocrinology 32:834–842CrossRefPubMedGoogle Scholar
  70. 70.
    Kumar G, Jones NC, Morris MJ, Rees S, O’Brien TJ, Salzberg MR (2011) Early life stress enhancement of limbic epileptogenesis in adult rats: mechanistic insights. PLoS ONE 6:e24033CrossRefPubMedPubMedCentralGoogle Scholar
  71. 71.
    Castro OW, Santos VR, Pun RY, McKlveen JM, Batie M, Holland KD et al (2012) Impact of corticosterone treatment on spontaneous seizure frequency and epileptiform activity in mice with chronic epilepsy. PLoS ONE 7(9):e46044CrossRefPubMedPubMedCentralGoogle Scholar
  72. 72.
    Sheline YI, Gado MH, Kraemer HC (2003) Untreated depression and hippocampal volume loss. Am J Psychiatry 160:1516–1518CrossRefPubMedGoogle Scholar
  73. 73.
    Sheline Y, Wang PW, Gado MH (1996) Hippocampal atrophy in recurrent major depression. Proc Natl Acad Sci USA 93:3908–3913CrossRefPubMedPubMedCentralGoogle Scholar
  74. 74.
    Bremner JD, Narayan M, Anderson ER, Staib LH, Miller HL, Charney DS (2000) Hippocampal volume reduction in major depression. Am J Psychiatry 157:115–118CrossRefPubMedGoogle Scholar
  75. 75.
    Öngür D, Drevets WC, Price JL (1998) Glial reduction in the subgenual prefrontal cortex in mood disorders. Proc Natl Acad Sci USA 95:13290–13295CrossRefPubMedPubMedCentralGoogle Scholar
  76. 76.
    Rajkowska G, Miguel-Hidalgo JJ, Wei J (1999) Morphometric evidence for neuronal and glial prefrontal cell pathology in major depression. Biol Psychiatry 45:1085–1098CrossRefPubMedGoogle Scholar
  77. 77.
    Cotter DR, Pariante CM, Everall IP (2001) Glial cell abnormalities in major psychiatric disorders: the evidence and implications. Brain Res Bull 55:585–595CrossRefPubMedGoogle Scholar
  78. 78.
    Cotter D, Mackay D, Chana G, Beasley C, Landau S, Everall IP (2002) Reduced neuronal size and glial cell density in area 9 of the dorsolateral prefrontal cortex in subjects with major depressive disorder. Cereb Cortex 12:386–394CrossRefPubMedGoogle Scholar
  79. 79.
    Salgado PC, Yasuda CL, Cendes F (2010) Neuroimaging changes in mesial temporal lobe epilepsy are magnified in the presence of depression. Epilepsy Behav 19:422–427CrossRefPubMedGoogle Scholar
  80. 80.
    Bilevicius E, Yasuda CL, Silva MS, Guerreiro CA, Lopes-Cendes I, Cendes F (2010) Antiepileptic drug response in temporal lobe epilepsy: a clinical and MRI morphometry study. Neurology 9(75):1695–1701CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2017

Authors and Affiliations

  1. 1.Department of NeurologyUniversity of Miami, Miller School of MedicineMiamiUSA

Personalised recommendations